Mapping the Multi-Organ miRNA-mRNA Regulatory Network in LPS-Mediated Endotoxemic Mice: Exploring the Shared Underlying Key Genes and Mechanisms

Abstract

BackgroundTo this day, the molecular mechanism of endotoxin-induced multi-organ failure has not been completely clarified. This study aimed to construct an miRNA-mRNA regulatory network and identify main pathways and key genes in multi-organ of LPS-mediated endotoxemic mice.MethodsPublic datasets from six mRNA and three miRNA microarray datasets were downloaded from the GEO website to screen final differentially expressed genes (FDEGs) and hub genes in the heart, lung, liver, and kidney of LPS-mediated endotoxemic mice. Functional and pathway enrichment analysis of FDEGs was used to identify the main pathways in multi-organ damage of LPS-treated mice. Finally, hub genes of each organ were intersected to obtain the key genes of multi-organ.ResultsFirstly, 158, 358, 299, and 91 FDEGs were identified in the heart, lung, liver, and kidney, respectively. The pathway enrichment analysis of the FDEGs then showed that the TNF signaling pathway, Toll-like receptor signaling pathway, and some viral-infection-related pathways (influenza A, measles, and herpes simplex) were the main pathways in multi-organ damage of LPS-mediated endotoxemic mice. Moreover, miRNA-mRNA or PPI regulatory networks were constructed based on FDEGs. According to these networks, 31, 34, 34, and 31 hub genes were identified in the heart, lung, liver, and kidney, respectively. Among them, nine key genes (Cd274, Cxcl1, Cxcl9, Icam1, Ifit2, Isg15, Stat1, Tlr2, and Usp18) were enriched in Toll-like receptor signaling pathway and chemokine signaling pathway. Finally, seven potential drugs were predicted based on these key genes.ConclusionThe shared underlying molecular pathways in endotoxin-induced multi-organ damage that have been identified include Toll-like receptor signaling pathway and TNF signaling pathway. Besides, nine key genes (Cd274, Cxcl1, Cxcl9, Icam1, Ifit2, Isg15, Stat1, Tlr2, and Usp18) and seven potential drugs were identified. Our data provide a new sight and potential target for future therapy in endotoxemia-induced multi-organ failure.

Nlrp3 Deficiency Alleviates Lipopolysaccharide-Induced Acute Kidney Injury via Suppressing Renal Inflammation and Ferroptosis in Mice

“…However, in our study, the CCL2 mRNA level did not significantly decline after Nlrp3 knockout, which was probably related to the large individual differences in the WT + LPS group. Another bioinformatics study showed that CXCL9 is one of the key genes involved in multiple organ injuries caused by LPS in mice [ 31 ]. While the renal interstitial infiltration was relatively mild due to the low dose of LPS, the results of inflammatory factors suggest that Nlrp3 deletion attenuated renal inflammation.…”

MSM Supplementation Is Associated with Reduced Inflammation and Improved Innate Immune Response following In Vitro LPS-Stimulation in Humans after a Bout of Downhill Running

“…A small increase in expression of CCR1, CCR2, and CCR6 persisted at 24 h. Given their respective roles in the mediation of PAMP response, a sustained elevation with MSM may reflect a beneficial response that allows for a more efficient immune response to additional DAMP signals. CXCL9 is a chemokine that is associated with skeletal muscle damage [34] and confers anti-microbial activity in the presence of IFN-gamma [35]. CFH (Factor H) down-regulates neutrophils and monocytes via a complement pathway [36] and may have anti-inflammatory activity [37].…”

miR-340-5p Alleviates Oxidative Stress Injury by Targeting MyD88 in Sepsis-Induced Cardiomyopathy

“…In in vitro experiments, miR-340-5p mimic pretreatment can alleviate the oxidative stress injury induced by LPS, suggesting that miR-340-5p can protect myocardial function by reducing the level of myocardial oxidative stress. In our previous bioinformatics analysis, we demonstrated that MyD88 may be the hub gene of SIC [ 23 ], and the predictive analytics showed that MyD88 is the target gene of miR-340-5p. In order to further investigate whether miR-340-5p affects the level of myocardial oxidative stress by regulating MyD88 in SIC, we confirmed the interaction of miR-340-5p with MyD88 via the dual-luciferase reporter assay and RNA pull-down assay.…”

“…The animals were divided into four groups: the control group, LPS group, miR-340-5p group, and miR-340-5p-combined LPS group. As previously described, mice were intraperitoneally injected with LPS (Sigma-Aldrich, 10 mg/kg) for 6 hours to establish the sepsis-induced cardiomyopathy model [ 23 ]. In the control group (OE-NC group), the mice were intramyocardial injected with 20 μ l (1 × 10 11 vg/mice) of Adenoassociated Virus- (AAV-) 9 negative control (Shanghai GeneChem Co., Ltd., China) at day 0 and were intraperitoneally injected with phosphate-buffered saline (PBS) buffer for 6 hours at day 21.…”

“…AbdAllah et al have found that a high circulatory MyD88 level is significantly correlated with the poor prognosis of neonatal sepsis [ 22 ]. Our previous transcriptome sequencing result analysis on a LPS-treated mouse heart suggested that the MyD88 gene is a key node gene of SIC [ 23 ]. In addition, through bioinformatics analysis, we predicted that miR-340-5p could interact with MyD88 3′UTR, and the site is conservative in different species.…”